Abstract
Human cytomegalovirus (HCMV) US2, US3, US6 and US11 act in concert to prevent immune recognition of virally infected cells by CD8+ T-lymphocytes through downregulation of MHC class I molecules (MHC-I). Here we show that US2 function goes far beyond MHC-I degradation. A systematic proteomic study using Plasma Membrane Profiling revealed US2 was unique in downregulating additional cellular targets, including: five distinct integrin α-chains, CD112, the interleukin-12 receptor, PTPRJ and thrombomodulin. US2 recruited the cellular E3 ligase TRC8 to direct the proteasomal degradation of all its targets, reminiscent of its degradation of MHC-I. Whereas integrin α-chains were selectively degraded, their integrin β1 binding partner accumulated in the ER. Consequently integrin signaling, cell adhesion and migration were strongly suppressed. US2 was necessary and sufficient for degradation of the majority of its substrates, but remarkably, the HCMV NK cell evasion function UL141 requisitioned US2 to enhance downregulation of the NK cell ligand CD112. UL141 retained CD112 in the ER from where US2 promoted its TRC8-dependent retrotranslocation and degradation. These findings redefine US2 as a multifunctional degradation hub which, through recruitment of the cellular E3 ligase TRC8, modulates diverse immune pathways involved in antigen presentation, NK cell activation, migration and coagulation; and highlight US2’s impact on HCMV pathogenesis.
Highlights
Human cytomegalovirus (HCMV) is the prototype betaherpesvirus and an important human pathogen
We developed ‘Plasma Membrane Profiling’ (PMP), an unbiased SILAC-based proteomics technique to ask whether MHC molecules are the only focus of these genes, or whether additional cellular immunoreceptors are targeted
All US2 substrates were degraded via the cellular E3 ligase TRC8, and in a remarkable example of cooperativity between HCMV immune-evasins, UL141 requisitioned US2 to target the NK cell ligand CD112 for proteasomal degradation
Summary
HCMV is the prototype betaherpesvirus and an important human pathogen. Following primary infection, HCMV persists for the lifetime of the host under constant control by the host immune system. Four genes clustered in the HCMV unique short (US) gene region use independent mechanisms to suppress MHC-I dependent antigen presentation to CD8+ cytotoxic T lymphocytes [6]. US2 and US11 both bind MHC-I in the lumen of the ER and hijack the mammalian ER-associated degradation (ERAD) machinery to promote retrotranslocation to the cytosol for proteasome degradation [11, 12]. US2 utilizes the cellular E3 ligase TRC8 (translocation in renal cancer from chromosome 8) to ubiquitinate and subsequently degrade MHC-I [13], whereas US11 uses a Derlin-1-associated ERAD complex centered around the newly characterized TMEM129 E3 ligase [14,15,16]. US3 retains MHC-II molecules in the ER while US2 initiates the retrotranslocation of MHC-II DR-α chain and DM-α chain from the ER back to the cytosol for subsequent degradation
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